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Sitaxsentan Phase 3 Trial Demonstrates Improved Walking Distance in Patients With Pulmonary Arterial Hypertension
The trial met its primary endpoint of improved six minute walk (6MW) distance in patients receiving a 100 mg dose of Thelin, with a placebo- subtracted improvement of 31.4 meters (p=0.03). A 50 mg dose of Thelin improved 6MW by 24.2 meters, and bosentan (Tracleer(R)), currently the only approved oral agent for treating PAH, improved 6MW by 29.5 meters. As expected, placebo patients worsened in 6MW over the 18-week period of the trial. World Health Organization (WHO) functional class also improved significantly at the 100 mg dose of Thelin versus placebo (p=0.04). There were five clinical worsening events in the 100 mg patient group, seven events in the 50 mg group, 15 events in the bosentan group, and 13 for placebo.
The 100 mg dose of Thelin continued to demonstrate an encouraging safety profile. Liver function abnormalities (elevation in liver enzymes to levels >3 times the upper limit of normal) occurred in 3% of patients in the 100 mg Thelin group, compared to 5% in the 50 mg Thelin group, 11% in the bosentan group and 6% in the placebo group. Premature discontinuations due to safety or efficacy occurred in four patients at the 100 mg Thelin dose, eight at the 50 mg Thelin dose, nine in the bosentan group and 11 in the placebo group. Of these patients, adverse events contributed to the discontinuation of two patients in the 100 mg Thelin group, four in the 50 mg group, six in the bosentan group and six in the placebo group.
No serious bleeding episodes were reported in the study. Three patients had bleeding episodes in the presence of elevated international normalized ratios (INRs), one each on placebo, 50 and 100 mg of Thelin. The most frequent adverse events that occurred in patients receiving Thelin, which were more common than in placebo-treated patients, were peripheral edema (100 mg), insomnia (50 mg), chest discomfort (50 mg), sinus congestion (100 mg), nausea (50 mg), upper abdominal pain (50 mg) and increased INR (100 mg).
"We are extremely pleased with the performance of Thelin in STRIDE-2," commented Bruce D. Given, M.D., President and Chief Executive Officer of Encysive Pharmaceuticals. "We will present more details from this trial at appropriate medical meetings over the next several months and we are now focused on filing a New Drug Application (NDA) with the U.S. Food and Drug Administration in April 2005 to seek marketing authorization. This NDA submission will be closely followed by marketing applications in Europe and other territories."
Additional Study Details
STRIDE-2 was an 18-week Phase III, randomized, double-blind, placebo- controlled safety and efficacy study of Thelin with an open-label bosentan arm in patients with PAH. Patients were randomized to receive one of four treatments: 50 mg of Thelin once daily, 100 mg of Thelin once daily, placebo once daily, or bosentan twice daily. A total of 246 patients were enrolled at 55 centers in North America, Europe, Israel and Australia.
Source: Encysive Pharmaceuticals